1. Field of the Invention
The present invention generally concerns the use of markers for the diagnosis or prognosis of peritoneal carcinoses and/or metastatic primary tumors and methods for the detection or prognosis of such diseases in biological samples, use of the markers as targets for therapeutic treatment of these diseases, and relevant pharmaceutical compositions and diagnostic kits.
2. Description of the Related Art
Tumors generally constitute sites of tissue proliferation that occur as a result of pathologically excessive cell growth. Tumor cells, or cancer cells, are cells that are genetically altered—e.g., through mutations—and, because of unlimited division and the capacity to spread via the lymphatic vessels and blood vessels and thus to colonize other tissues, cause the formation of tumors.
Therefore, in addition to altered morphology, tumor cells are usually characterized by nuclear polymorphism and tend to form foci. This means that they are no longer inhibited from contact and can therefore form adhesions. Moreover, tumor cells frequently cease to function normally and often can no longer be detected because of dedifferentiation of their original tasks. In addition, the cell membranes of tumor cells show new, so-called tumor antigens or tumor-associated antigens that can be used as markers to diagnose tumors.
For example, the altered behavior of tumor cells and the presentation of tumor-associated antigens in the cell membrane are attributable to changes in gene expression and in the metabolism of the tumor cells, which also results in altered signal transduction. On the other hand, this altered behavioral pattern and expression pattern is associated with the occurrence of markers specific to the tumor cells, which can be used to detect the presence of tumors in the body of a patient.
Moreover, an important aspect of malignant tumors is the formation of metastases, also referred to as metastasis. In this process, tumor cells move from their primary location, which is referred to as the primary tumor, via blood or lymphatic vessels to organs and tissues showing no primary disease, where colonization of the cells occurs to form metastases, i.e. daughter tumors. This invasion allows tumors cells to spread throughout the body, and even to colonize tissues far removed from the primary tumor, in which new tumors can then be formed.
The occurrence of malignant tumors, i.e. carcinogenesis, can be divided into three phases: in the initial phase, the cell is irreversibly transformed, e.g. specifically via the activation of protooncogenes, via carcinogenic hormones, oncogenic viruses, genetic defects in the DNA repair system, mutations, acquired or congenital immune defects, radiation, or carcinogens. In the subsequent latent phase, the transformed cells proliferate through additional involvement of carcinogens or other factors, and in some cases, metastases may already form in this phase. Finally, in the manifestation phase of tumor formation, malignant forms that tend to grow in an infiltrative manner and form metastases develop from early forms or even from initially benign tumors.
Early detection and diagnosis of tumors, particularly metastatic tumors, is of vital importance so that treatments can be instituted as early and quickly as possible. The earlier the tumor is detected, the more favorable the prognosis for cure or successful treatment. At present, a number of tumor markers are in clinical use that, as mentioned above, constitute e.g. substances and or cellular changes whose qualitative and/or quantitative analysis can provide information on the presence, the course, or the prognosis of malignant tumors. As mentioned previously, such tumor markers may be membrane-bound tumor antigens, as well as receptors and cell markers that indicate the increased expression of oncogenes and monoclonal cell growth. Moreover, another possibility is provided by substances for tumor diagnosis that, compared to samples from healthy patients, can be found in elevated concentrations in tissue samples from diseased patients, e.g. in the serum, urine, and/or other body fluids, or in tissues. Such substances are synthesized and/or secreted by the tumor tissue, released by oncolysis, or form when the organism reacts to a tumor.
Types of tumors that usually have a fatal outcome include peritoneal carcinoses, which frequently develop in patients with gastric tumors, often following surgery. Peritoneal carcinoses are formed when cancer cells from gastric tumors disseminate throughout the abdominal cavity, i.e., these tumors are metastatic primary tumors. To date there is virtually no drug available for this type of tumor, making it an ominous disorder, particularly in view of the extremely low survival rate (5%) in patients with peritoneal carcinoses.
There is also no known marker available to date that would allow the prediction of primary tumor metastasis for many other metastatic primary tumors, particularly of the gastrointestinal tract. The gastrointestinal tract comprises the esophagus, stomach, small intestine, large intestine (colon), and pancreas, as well as the duodenum, jejunum, and ileum, which are the subdivisions of the small intestine. Tumors of the gastrointestinal tract are among the most common causes of cancer fatality in humans.
Using tumor markers, it is possible, for example, to conduct early examination of primary tumors in order to determine whether they are metastatic, which can allow early intervention, and in favorable cases, prevention of metastasis.